tbuckley/cabot-search huggingface dataset:
Phase I/II combination study of tifcemalimab with toripalimab in patients with refractory extensive stage small cell lung cancer (ES-SCLC).
Authors: Ying Cheng, Jie Wang, Yan Yu, Qiming Wang, Runxiang Yang, Dongqing Lv, Bing Xia, Tienan Yi, Chong Li, Xicheng Wang, Wei Zhang, Liang Han, Xiaoqing Liu, Minjie Shen, Jing Xu, Peng Xue, Weihua Wang
Journal: Journal of Clinical Oncology (2023)

8579 Background: The B- and T-lymphocyte attenuator (BTLA) is a novel inhibitory co-signaling receptor expressed on B cell, T cells and NK cells. Co-blockade of the BTLA and PD-1 pathways improved antigen specific anti-tumor T cell response. Tifcemalimab (JS004 or TAB004) is a humanized IgG4 monoclonal antibody with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand HVEM. In previous phase I studies, tifcemalimab has shown preliminary anti-tumor activities as monotherapy or in combination with toripalimab (anti-PD-1) with a manageable safety profile in patients with advanced malignancies. Methods: Eligible ES-SCLC patients refractory to prior therapies were enrolled in this I/II study (NCT05000684). Patients received 200mg tifcemalimab and 240mg toripalimab intravenously once every three weeks until disease progression, intolerable toxicity or 2 years of treatment. Study objectives included safety, anti-tumor activity and correlative biomarkers. Results: As of Jan 31, 2023, a total of 43 ES-SCLC patients refractory to prior therapy were enrolled. The median age was 60.0 (range 38-75) years. The median prior line of therapy was 1 and 14 (32.6%) patients received prior anti-PD-1/L1 treatment. By the cut-off date, the median follow-up duration was 12.1 weeks. Thirty-two (74.4%) patients experienced treatment-emergent adverse events (TEAEs); 12 (27.9%) patients experienced grade ≥ 3 TEAEs. The most common TEAEs were hyponatraemia (16.3%), alanine aminotransferase increased (14%), aspartate aminotransferase increased (14%), and blood creatine phosphokinase increased (14%). Three (7.0%) patients experienced treatment-related adverse events (TRAEs) led to interruption of study drugs and no TRAEs led to discontinuation of study drugs were reported. Fifteen (34.9%) patients experienced immune related AE (irAEs), and 2 (4.7%) patients experienced grade ≥ 3 irAEs. Among 38 efficacy evaluable patients, the ORR was 26.3% and the DCR was 57.9%. The ORR was 8.3% in immunotherapy treated patients and 40.0% in immunotherapy naïve patients. By the cut-off date, 70.0% of the responses were ongoing and the median duration of response was not reached. Tumor expression of HVEM and PD-L1 was evaluated to explore the correlation with clinical response. Conclusions: Tifcemalimab in combination with toripalimab were well tolerated in patients with refractory ES- SCLC. Further clinical evaluation of this combination treatment in SCLC is warranted. Clinical trial information: NCT05000684 .
Long term efficacy of psilocybin in patients with cancer and major depressive disorder (MDD).
Authors: Manish Agrawal, Sarah Shnayder, Heather Honstein, Ezekiel J. Emanuel, Paul M. Thambi
Journal: Journal of Clinical Oncology (2023)

12021 Background: Up to 25% of people living with cancer have depression. Existing psychological interventions have limited efficacy in treating depression. Psilocybin, a 5-hydroytrptamintergic psychedelic, coupled with group therapy is safe and effective in ameliorating symptoms of depression (Agrawal et al, ASCO 2022). Response to psilocybin treatment was observed in 83.3% of patients at 8 weeks, and 50% of patients showed full remission of depressive symptoms. This study evaluates the efficacy of psilocybin-assisted group therapy in relieving depression in cancer patients over 18 months. Methods: Adults with curable or metastatic cancer and MDD (according to DSM-5) underwent psychological assessments at baseline. They were treated with single-dose psilocybin 25 mg administered simultaneously in group cohorts of 3-4, supported with group and individual psychological therapy, and evaluated at 8 weeks and 18 months. Primary objectives were long-term effectiveness on depression and anxiety severity (as measured by change in Montgomery Asberg Depression Rating Scale [MADRS] and Hamilton Depression Rating Scale [HAM-A] scores by independent rater assessments) as well as clinical response (≥50% decrease in MADRS total score from baseline to 18 months) and remission (defined as patients with a MADRS total score ≤10 at 18 months). Results: Of 30 patients enrolled in the parent study, 2 died and 4 were lost to follow-up. Clinical response was demonstrated in 18/28 patients (64.2%) from baseline to 18 months follow-up (see table); 16/28 patients (57.1%) demonstrated remission of depression at 18 months. In 24 evaluable patients, continued reduction in mean depression severity scores was also demonstrated from baseline to week 8 (MADRS by 20.6 points [95% CI 23.2, 18.0, p &lt; 0.001] and HAMA-A by 16.7 points [95% CI 19.7, 13.7, p &lt; 0.001]) and from baseline to 18 months (MADRS by 16.7 points [95% CI 20.4, 12.9, p &lt; 0.001] and HAMA-A by 14.4 points [95% CI 17.3, 11.4, p &lt; 0.001]). Conclusions: Long-term follow-up suggests continued robust clinical response and remission from depression with a single dose of psilocybin and simultaneous psychological support in patients with cancer and MDD. These findings indicate psilocybin may play a role in treatment of depression in cancer patients, and further investigations are ongoing. [Table: see text]
Failure rates of mutation-based ctDNA assays in lung cancer treatment monitoring.
Authors: Jillian Phallen, Jamie E. Medina, Niti U. Trivedi, Lorenzo Rinaldi, Victor E. Velculescu, Peter Brian Bach, Alessandro Leal
Journal: Journal of Clinical Oncology (2023)

e18752 Background: Despite the wide adoption of noninvasive liquid biopsy approaches for cancer genotyping, little is known about the longitudinal performance of these assays for monitoring therapeutic responses in patients with advanced disease. Here, we report results of a pooled analysis that collects existing evidence regarding the failure rates of circulating tumor DNA (ctDNA) assays designed for therapeutic monitoring in patients with advanced or metastatic lung cancer. Methods: We searched PubMed for original studies published between February 2012 and January 2022, following these inclusion criteria: (1) Adults older than 18 years old with advanced or metastatic lung cancer treated with chemotherapy, targeted therapy, or immunotherapy; (2) Tumor-informed or plasma-only circulating tumor DNA assays based on droplet digital PCR (ddPCR) or targeted deep sequencing technologies for the detection of tumor-specific allele fractions; (3) Measurement of circulating tumor DNA levels at sequential timepoints. We defined failures as a lack of detectable mutant allele fraction (MAF) in patients with metastatic lung cancer in samples collected before treatment initiation. Two reviewers independently screened studies, extracted data, assessed the risk of bias, and evaluated the quality of evidence. Divergences were resolved by a third independent reviewer reaching a consensus. Study quality assessment covered: (1) representativeness of patient population, (2) risk of funding bias, (3) description of ctDNA analysis and outcomes, and (4) statistical quality and interpretation. Results: From 142 studies retrieved by an automated PubMed query, we extracted data from 42 studies which fulfilled the eligibility criteria - 11 registered trials, 31 prospective/retrospective cohorts. MAF levels in the circulation were measured using PCR-based assays (23/42, 55%); the remainder used NGS-based approaches (19/42, 45%). The median number of targeted genes was 1 (range 1-6) vs 73 (range 36-214), respectively. The median number of samples analyzed per study was 79 (range 3-334). On average, 31% of samples collected before treatment did not have a detectable MAF in any of the target genes analyzed, despite the high disease burden typically experienced in patients with metastatic lung cancer. Only 57% of PCR-based and 78% NGS-based studies succeeded in providing molecular response assessment metrics. We identified 10/42 studies with critical quality assessment concerns and 18 studies had funding provided by a company with investments in the commercial cfDNA assay. Conclusions: Available liquid biopsy assays that report tumor-specific mutations have a high rate of failure for measuring disease burden and response outcomes during therapy. Approaches that could be reliably used for monitoring patients with advanced cancers undergoing treatment are needed to improve patient care.
Curability of multiple myeloma (MM) based on relative survival rate (RSR) in patients (pts) treated on earlier total therapy (TT) protocols.
Authors: Samer Al Hadidi, Obada Ehab Ababneh, Carolina D. Schinke, Sharmilan Thanendrarajan, Clyde Bailey, Maurizio Zangari, Guido Tricot, John D. Shaughnessy, Fenghuang Zhan, Jeffrey Sawyer, Frits van Rhee, Bart Barlogie
Journal: Journal of Clinical Oncology (2023)

8059 Background: Long term overall survival (OS) follow-up data in pts with MM treated on clinical trials is limited. TT approach uses all MM-active drugs upfront to target drug-resistant subclones during initial treatment to prevent later relapse. We report the longest follow up of MM trials (TT1 (NCT00580372), TT2 (NCT00083551), TT3a (NCT00081939) and TT3b (NCT00572169)) reported to date with RSRs to assess for curability. Methods: Pts treated on TT1, TT2, TT3a and TT3b were followed at the University of Arkansas for Medical Sciences after completion of therapy including multi-agent chemotherapy, high dose melphalan followed by tandem autologous stem cell transplantation (ASCT) and fixed duration maintenance therapy with introduction of thalidomide (thal) (TT2+thal vs TT2-thal), bortezomib (TT3a) and lenalidomide (TT3b). Expected survival rate was defined as probability of a population surviving from yr to yr. RSR was defined as ratio between observed survival of trials to expected survival in population adjusting for age and sex based on enrollment year. Data cut-off was October 10, 2022. Results: 1379 pts were enrolled (TT1:231, TT2:668, TT3a:303, TT3b:177) with median follow up duration of 16.6 years (yrs) (TT1:25 yrs, TT2:18.4 yrs, TT3a:16.2 yrs, TT3b:14.2 yrs). 10-yr PFS increased from 8.8% (TT1) to 15.5% (TT2-thal) to 25.1% (TT2+thal) to 32.9% (TT3a) to 42.4% (TT3b). Median OS improved over time (TT1:5.8 yrs, TT2:10.4 yrs, TT3a:11.9 yrs, TT3b:10.1 yrs). 15-yrs OS improved from 24.2% in TT1, 33% in TT2, 40% in TT3a and 37% in TT3b. 20-yr OS is 24.4% for pts treated on TT2 protocol. Outcomes were better for standard risk disease defined by low-risk gene expression profiling (GEP) with 20-yrs OS of 30% in TT2 and 15-yrs OS of 45% in TT3a. RSRs approach 1 at 10-15 yrs for TT1, but this occurs earlier, at 5-10 yrs, for TT2+Thal, TT3a and TT3b [Table]. No difference in RSR between TT3a and TT3b was noted. Relative excess risk (RER) showed an estimated 23%, 44% and 54% lower excess mortality when comparing TT2 (+ thal), TT2 (-thal) and TT3a with TT1, respectively. Conclusions: In the longest follow up duration of any MM clinical trial, a subset of MM pts are cured as evidenced by RSRs approaching 1. Approximately one third of pts treated on TT2 protocol and one-half pts treated on TT3a are alive at 20 year and 15 yrs from initial diagnosis, respectively. Incorporation of immunomodulatory drugs and proteasome inhibitors along with tandem ASCT resulted in cumulative improvement of OS as evidenced by lower RER of mortality. Clinical trial information: NCT00580372 , NCT00083551 , NCT00081939 , NCT00572169 . [Table: see text]
NEO-CESQ study: Neoadjuvant plus adjuvant treatment with cemiplimab in surgically resectable, high risk stage III/IV (M0) cutaneous squamous cell carcinoma.
Authors: Paolo Antonio Ascierto, Paolo Bossi, Mario Mandalà, Paola Queirolo, Francesco Spagnolo, Franco Bassetto, Vittorio Rampinelli, Francesco Giovacchini, Elisabetta Pennacchioli, Corrado Caraco, Gianpiero Parrinello, Domenico Mallardo, Diana Giannarelli, Claudia Trojaniello, Daniela Massi, Vanna Chiarion-Sileni
Journal: Journal of Clinical Oncology (2023)

9576 Background: In the last years, the treatment of locally advanced and/or metastatic cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of cemiplimab, an anti-PD-1 antibody, which showed a 50% overall response rate and long term benefit (1). Recently, a phase II trial of neoadjuvant cemiplimab in resectable CSCC patients (2), showed a major pathological response (MPR) rate of 63.3%. In the current multicenter, phase II trial we evaluated the efficacy of neoadjuvant plus adjuvant immune checkpoint inhibitor in patients with surgically resectable, high-risk stage III/IV (M0) CSCC. Methods: Patients with surgically resectable high-risk stage III/IV (M0) CSCC received cemiplimab at a dosage of 350 mg every 3 weeks for two cycles prior surgery and for one year after surgery. The study primary endpoint was MPR [pathological complete response (pCR) or near pCR ( &lt; 10% remaining viable tumour cells in the surgical pathology sample)] per independent central pathology review. Key secondary endpoints included recurrence-free survival (RFS), overall survival (OS), safety and the analysis of predictive biomarkers. Results: From May 2021 to October 2022 twenty-three patients were enrolled in 6 centers. pCR was observed in 9 (39%) patients and near pCR in 2 (8%) patients, while pathological partial response (10-50% remaining viable tumour cells) and no pathologic response was observed in 1 patient and 11 patients, respectively. At data lock of 31 st January 2023, only one patient was discontinued due to clinical progression. Furthermore, it was observed n = 60 (57%) any adverse events (AE) and n = 29 (30%) treatment-related AE. No any G3/G4 AE were observed. Conclusions: Neoadjuvant cemiplimab induced a pathological response in 52% of stage III/IV (M0) CSCC patients with a MPR in 48%. The study is still ongoing to evaluate the impact of combined neoadjvuant and adjuvant immunotherapy on RFS and biomarkers analysis. Clinical trial information: NCT04632433 .
Real-world treatment patterns and clinical outcomes among subgroups of BRAF-positive metastatic melanoma patients treated with dabrafenib + trametinib.
Authors: Zeynep Eroglu, Jackson Tang, Clare Byrne, Lucy Connolly, Rohan Shah, Thach-Giao Truong
Journal: Journal of Clinical Oncology (2023)

9521 Background: Whether disease attributes such as tumor burden or central nervous system (CNS) metastases can affect outcomes for patients with BRAF+ metastatic melanoma (MM) is currently unclear. This study examined real-world patient characteristics, treatment patterns, and clinical outcomes among subgroups of patients with BRAF+ MM treated with dabrafenib + trametinib (dab/tram) in the United States. Methods: This retrospective cohort study used the nationwide Flatiron Health electronic health record-derived de-identified database from 1/1/2014 to 9/30/2021. Included patients were aged ≥18 years with a diagnosis of BRAF+ MM and received first-line (1L) dab/tram. Patients were stratified into 4 subgroups: high tumor burden (HTB; ≥3 sites of metastasis and lactate dehydrogenase [LDH] ≥333 IU/L), low tumor burden (LTB; &lt;3 sites of metastasis and LDH &lt;333 IU/L), with CNS metastases (prior to 1L dab/tram), and without CNS metastases (prior to 1L dab/tram). Patient characteristics and treatment patterns were evaluated descriptively. Given the potential patient overlap between subgroups, no comparative statistics were conducted. Real-world progression-free (rwPFS) and overall survival (OS) were explored from dab/tram initiation. Results: Among 460 included patients (mean age 60 years, 64% male), 66 (14%) had a HTB, 69 (15%) had a LTB, 164 (36%) had CNS metastases, and 296 (64%) did not. Patient characteristics were comparable across the subgroups. Over 60% of HTB patients had documented metastases in each of the liver, lung, bone, lymph nodes, and other sites. Only lung metastases had &gt;60% prevalence among patients with a LTB. Overall, 51% of the included patients went on to receive a second-line therapy; LTB patients and those without CNS metastases had a longer time to next therapy. The median rwPFS and OS were significantly shorter among patients with a HTB vs LTB, and among patients with vs without CNS metastases (Table). Conclusions: Both tumor burden and presence of CNS metastases appear to have a significant impact on survival among BRAF+ MM patients treated with 1L dab/tram. With growing use of 1L immunotherapy in MM, 1L BRAF/MEK inhibitors are increasingly being used in patients with a worse prognosis, which may explain the lower rwPFS and OS with dab/tram when compared with clinical trials. [Table: see text]
A nationwide population based primary CNS lymphoma (PCNSL) analysis: Do Hispanics have better outcomes?
Authors: Ysaith Orellana, Kana Lucero, Qianqian Liu, Joel Michalek, Adolfo Enrique Diaz Duque
Journal: Journal of Clinical Oncology (2023)

10560 Background: Over the last decade, overall survival (OS) of PCNSL patients has increased from 12.5 months to 26 months (N. Oncol, PMID 30418592). One study examined the incidence of PCNSL in the Hispanic (HI) population in Texas (Cureus, PMID: 33042676), but a national study is needed to understand ethnic disparities, as many HI face barriers to health care access (Natl Cance Inst Monogr, PMIDL 8562207). This study aims to understand demographics, treatment patterns, and outcomes of HI and Non-Hispanic (NH) patients with PCNSL nationally. Methods: Data analyzed on PCNSL patients in the United States (US) was reported to the Surveillance, Epidemiology, End Results (SEER) 18 database between 2000 and 2018. Racial groups analyzed included NH whites, HI whites, Blacks, and Asian/Pacific Islanders (PI). Patient characteristics, age-adjusted incidence rate, and survival rate were compared across ethnic groups (HI vs. NH). Stratification by age, gender, and stage at diagnosis was considered. Data was stratified using Kaplan-Meier and Cox regression analyses to compare OS between HI and NH. Multivariate analysis and propensity score matching was performed with adjustment for age, stage, and B-symptoms. Results: Of 5819 PCNSL patients, 15% were HI, and 85% NH. 57% were male compared to 51% of NH. As compared to NH at diagnosis, HI patients were younger, 59 years vs. 66 years(y) (p&lt;0.001); the majority of HI (42%) were diagnosed in the age bracket of 60-80y (p&lt;0.001). Approximately 30% of HI were diagnosed in 2015-2018, while most of NH (29%) were diagnosed in 2010-2014 (p=0.054). With 52% of HI being diagnosed at &lt;60y, only 32% in NH. As for race, most of HI and NH were White (97% vs. 79%), followed by Black (1% vs. 8%). On survival analysis, the survival probability at 2, 5, and 10y of HI vs. NH were (0.507 vs. 0.441), (0.395 vs. 0.322), and (0.237 vs. 0.225), respectively. The median survival time was 2.1y for HI vs. 1.2y for NH. There was an OS difference favoring HI (p=0.0009). On multivariate analysis, when adjusted for age, patients with PCNSL between 60-80y and above have 3.4 times more likely to die from disease after diagnosis with HR 3.4 (95% CI:2.9-4) and 1.7 (95% CI: 1.6-1.9). Conclusions: Our study demonstrates statistically longer median survival and OS favoring the HI population. The younger age of diagnosis in HI patients could be a factor in their survival probability for PCNSL, given that both HI and NH received similar treatment and had a similar staging. However, additional studies would be needed to validate this observation and determine other biological or socioeconomic factors that may play a role. [Table: see text]
Clinical implications of universal germline testing in breast cancer patients in an Arab population: The Jordanian Exploratory Cancer Genetics (Jo-ECAG) study.
Authors: Hikmat Abdel-Razeq, Sarah M. Nielsen, Baha' Sharaf, Hira Bani Hani, Emily M Russell, Brandie Heald, Mais Alkyam, Lama Abujamous, Rawan Mohammed Mahmoud Mustafa, Khansa Al-Azzam, Shatha Elemian, Hala Abu-Fares, Majd Hamed Allah, Zeidan Zeidan, Robert Luke Nussbaum, Edward D. Esplin
Journal: Journal of Clinical Oncology (2023)

e22535 Background: Germline genetic testing (GGT) for breast cancer (BC) has implications for surgical decision-making, treatment selection, clinical follow-up and cascade testing. As uptake of GGT increases globally, it is important to examine its impact on clinician decision-making, particularly in different ethnic groups. Methods: The Jo-ECAG Study consisted of unselected, newly diagnosed cancer patients (pts) from a single center in Jordan. Pts were classified as meeting (in criteria, IC) or not meeting (out of criteria, OOC) National Comprehensive Cancer Network (NCCN) v.1.2020 GGT criteria. Pts underwent a 84 gene test with clinician-reported outcomes collected &gt;2 months post GGT. Analysis was limited to pts with BC. Pts with one PGV in a gene associated with autosomal recessive inheritance (“carriers”) were excluded from overall PGV count. Blank responses were considered uninformative. Descriptive statistics and Fisher’s exact test were employed. Results: 1648 (21 male) Arabic pts with BC, 36% metastatic, with a mean age at diagnosis of 50.5 were tested; 67% were IC. 212 PGVs were identified in 202 (12%) pts, with a significantly higher rate in IC vs. OOC pts (14% vs. 8%, p=0.0002). PGVs were most common in BRCA1/2 (4%), APC I1307K (4%), and other BC-associated genes such as ATM, CHEK2, PALB2 and TP53 (collectively, 3%). 2% of pts were carriers and 57% had uncertain results. Among pts with PGVs and informative responses (Table), 18% had changes to treatment (11% OOC) and 82% to surveillance/follow up (16% OOC) based on GGT results. Genetic counseling and/or GGT was recommended for relatives of &gt;90% of PGV and carrier pts. No changes to treatment or follow-up were made for pts with negative or uncertain results. Conclusions: 1 in 8 Jordanian BC pts had a PGV identified, with a similar breakdown of PGVs observed in other ethnic cohorts, aside from a higher percentage of APC I1307K. Both treatment and surveillance/follow-up decisions were impacted by GGT results. Appropriately treatment or management was not escalated for pts with negative or uncertain results. [Table: see text]